The objectives of the proposed research are to develop therapeutic drug regimens that will have use in the treatment of cancer in man on the basis of pharmacological and biochemical information on the mechanism of drug action, with particular emphasis on: (a) characterization of the metabolic alterations responsible for cell death following exposure to chemical stress, (b) exploitation of possible neoplastic cellular sites of vulnerability by chemical modification of existing agents having some clinical efficacy, as well as further design and synthesis of new drugs based upon biochemical and pharmacological principles, and (c) the selection, on the basis of metabolic action, of drugs to employ in combination, thereby gaining increased therapeutic efficacy. Research emphasis is being placed upon the following: (a) alpha-(N)-heterocyclic carboxyaldehyde thiosemicarbazones, in an effort to develop a second generation inhibitor of ribonucleotide reductase with clinical potential, and the importance of inhibition of pyrimidine nucleoside kinase and RNA synthesis by these agents; (b) quinone and nitro-substituted derivatives which function as bioreductive alkylating agents; (c) the mechanism by which neoplasic cells attain resistance to the 6-thiopurines; (d) development and study of the biochemical mechanism of action of aryl sulfonyl hydrazones of heterocyclic N-oxides; (e) effects of anticancer agents and other metabolic inhibitors on surface membranes of neoplastic cells stressing the action of adriamycin, 6-thioguanine, arabinosylcytosine and 2-deoxy-D-glucose; (f) the role of glycosaminoglycans in murine melanoma metastases; and (g) the development and mechanism of action of inducers of differentiation of neoplastic cells.